Expanded tracts of CAG trinucleotide repeats, encoding polyglutamine, are now known to be the cause of several neurodegenerative diseases, among which are Huntington's Disease (HD; Huntington's Disease Collaborative Research Group, 1993, Cell, 72: 971-983) and several types of ataxia, including spinal and bulbar muscular atrophy (La Spada et al., 1991, Nature Genetics, 6: 14-18), dentatorubral-pallidoluysian atrophy (Koide, 1994, Nature Genetics, 6: 9-13; Nagafachi et al., 1994, Nature Genetics, 6: 14-18), and five dominantly inherited ataxias-spinocerebellar ataxia (SCA) types 1-3 (Imbert et al., 1996, Nature Genetics, 14: 285-291; Kawaguchi et al., 1994, Nature Genetics, 8: 221-228; Orr et al., 1993, Nature Genetics, 4: 221-226; Pulst et al., 1996, Nature Genetics, 14: 269-276; Sanpei et al., 1996, Nature Genetics, 14: 277-284), 6 (Zhuchenko et al., 1997, Nature Genetics, 15: 62-69) and 7 (David et al., 1997, Nature Genetics, 17: 65-70). These devastating autosomal dominant inherited disorders are characterized by impaired motor control and, in some cases, varying degrees of psychatric and cognitive deficiency (Huntington G., 1872, "On chorea", Med. Surg. Rep., 26: 317-321). Expansion of the glutamine-encoding sequence appears to result in a toxic gain of function that is selectively deleterous to the neurons affected in these diseases (Paulson and Fischbeck, 1996, Ann Rev. Neurosci., 19: 79-107). The genes which are linked to the risk of such neurological disease encode proteins that share no significant sequence homology with each other with the exception of the abnormally long polyglutamine regions.
Expression of truncated cDNAs encoding mostly expanded CAG repeats has been shown to induce cell death, but this effect is not seen when full-length proteins comprising the repeats are produced (Davies et al., 1997, Cell, 90: 537-548; Ikeda et al., 1996, Nature Genetics, 13: 196-202); therefore, it has been hypothesized that a truncated protein fragment derived from the full-length proteins in each of these disorders may be responsible for the as yet unidentified toxic gain of function leading to the degeneration of different neuronal populations characteristic of each disorder.
Defects in the gene encoding the protein Huntingtin are linked to the development of HD.
Expression of an allele of exon 1 of this gene, which allele contained greater than 21 CAG repeats, has been found to be sufficient to induce pathogenesis and clinical symptoms resembling those of HD in transgenic mice (Bates and Davies, 1997, Mol. Med. Today, 3: 508-515). The proteins with expanded polyglutamine repeats have been observed to form aggregates or cytoplasmic and nuclear inclusions in cultured cells overexpressing a truncated MJD protein with an expanded polyglutamine (Ikeda et al., 1996, supra), in transgenic mice expressing a truncated Huntingtin (Bates and Davies, 1997, supra), Drosophila expressing a truncated human ataxin-3 (Warrick et al., 1998, Cell, 93: 939-949), and in postmortem SCA 3 patient brain (Paulson et al., 1997, Neuron, 19: 333-344); in non-human models, such aggregates and inclusions resemble those observed in sectioned brain tissue derived from affected humans. It has been proposed that such abnormal inclusions may engage in inappropriate protein-protein interactions which lead to cell death. Neither the timing of formation of such inclusions (i.e., whether it preceeds or follows induction of the death program) nor the nature of any causal role for these structures in neurotoxicity has as yet been determined.
There is need in the art for methods and reagents directed at the inhibition of polyglutamine-mediated cell death.